International Epidemiological Association 2001
International Journal of Epidemiology 2001;30:1309–1313 Effect of prenatal treatment on the risk of intracranial and ocular lesions in children with congenital toxoplasmosis
Background Hydrocephalus, intracranial calcification and retinochoroiditis are the most common
manifestations of tissue damage due to congenital toxoplasmosis, but the effectof prenatal treatment on these outcomes is unclear. We aimed to determine theeffect of prenatal treatment for toxoplasmosis on the risk of intracranial andocular lesions in congenitally infected children at 3 years of age.
A cohort of mothers identified during pregnancy with toxoplasma infection andtheir 181 liveborn children with confirmed congenital toxoplasmosis was retro-spectively analysed to determine the presence of intracranial and ocular lesions. As few women are not treated, we compared the effects of the treatment potency(pyrimethamine-sulfadiazine versus spiramycin or no treatment), and the timingof treatment, on the risks of intracranial lesions, time to detection of ocular lesions,and detection of any lesions (intracranial or ocular) by 3 years of age. Analysestook account of the gestation at maternal seroconversion.
There was no evidence for an effect of pyrimethamine-sulfadiazine on intracranial,ocular or any lesions by 3 years: odds ratio (OR) for any lesions 0.89 (95% CI : 0.41,1.88). There was no evidence of an effect of delayed treatment on ocular lesions(hazard ratio = 0.69, 95% CI : 0.28, 1.68) or any lesions by 3 years of age (OR = 0.44,95% CI : 0.16, 1.19).
Conclusions Our study failed to detect a beneficial effect of early or more potent anti toxo-
plasma treatment on the risks of intracranial or ocular lesions in children withcongenital toxoplasmosis. However, larger, prospective studies, which determinethe effect of prenatal treatment on long-term developmental outcomes are requiredto justify changes in clinical practice.
Congenital toxoplasmosis, prenatal treatment, intracranial calcification, retino-choroiditis
The aim of prenatal treatment for infection with Toxoplasma
age in 33% (28/85) of congenitally infected children followed in
gondii is to prevent neurological or visual impairment in infected
three population-based cohort studies.3–5 Of the 28 with lesions,
children either by preventing mother to child transmission 3 (4%) had severe neurological impairment. Retinochoroidalof infection, or, once fetal infection has occurred, by limiting
lesions have been reported in 16% (14/85) children at 1–6 years
cell damage caused by the parasite.1,2,pp.173–75 In this report,
old,3–5 of whom up to half may have permanent visual impair-
we present results on the effect of prenatal treatment on lesions
ment, due to the size of the lesion and involvement of the macular
attributable to parasite-induced cell damage in children with
area.3–6 Information is lacking on the risk of developmental
confirmed congenital toxoplasmosis. The lesions most com-
impairment in children with intracranial or ocular lesions. How-
monly associated with congenital toxoplasmosis are intracranial
ever, many appear to develop normally6,7 and a small study
calcification or hydrocephalus, which are usually detected during
comparing 17 congenitally infected children and their siblings
infancy, and retinochoroiditis, which may appear at any age.2
raises the possibility that impairment may be worse in those
Intracranial and/or ocular lesions were detected before school
with ocular than intracranial lesions (R Eaton, New EnglandNeonatal Screening Program, personal communication).
The effect of prenatal treatment for toxoplasmosis on intra-
Centre for Paediatric Epidemiology and Biostatistics, Institute of Child Health,London, UK.
cranial or ocular lesions is uncertain. In a study of 144 consecutive
women referred to five fetal medicine centres, including 64
was recorded for analysis. We did not analyse the effect of treat-
with infected children, Foulon et al.8 found a reduction in the
ment on recurrence of lesions or on the size or site of lesions.
risk of lesions at 1 year of age in children born to women given
Congenital toxoplasmosis was diagnosed if there was persist-
any prenatal treatment compared with those not treated (odds
ence of specific IgG antibodies beyond 12 months of age.
ratio [OR] = 0.3; 95% CI : 0.10, 0.86). However, this study and
Absence of congenital toxoplasmosis was based on a decline in
a case-control study of 103 infected children,9 found no evidence
IgG specific antibody beyond detectable levels after discontinua-
for an effect of the more potent regimen of pyrimethamine-
tion of treatment. All mother-child pairs in which infection
sulfadiazine compared with spiramycin alone. Both studies
status was unknown were excluded from the analysis.
endeavoured to account for the effect of gestation at maternalinfection10 but failure to exclude women referred due to fetal
Postnatal treatment
abnormalities may have overestimated the risk of lesions in
Neonates with suspected infection were prescribed pyrimethamine
(3 mg/kg/3 days) and sulfadiazine (75 mg/kg/day) for 3 weeks,
We investigated the effect of prenatal treatment on the risk of
followed by spiramycin (0.375 × 106 units/kg/day) for 2–5 weeks,
signs in a cohort of children with congenital toxoplasmosis born
followed by pyrimethamine (6 mg/kg/10 days) and sulphadoxine
to infected women identified in Lyon, France. As few women
(125 mg/kg/10 days) with folinic acid for at least 12 months.
received no treatment, we examined whether the risk of lesions
All other infants received spiramycin alone pending further
was related to the potency of treatment used or to the interval
evidence of congenital infection status.
between maternal seroconversion and the start of treatment. Analysis
We investigated the effect of prenatal treatment in two ways. First, we compared the risk of lesions in children born to
Patients
women treated with spiramycin with those treated with
The study is based on liveborn children with congenital toxo-
pyrimethamine-sulfadiazine or not treated. We hypothesized
plasmosis of women who were prospectively identified with
that pyrimethamine-sulfadiazine would be more effective in
toxoplasma infection by the toxoplasma reference laboratory in
reducing the risk of lesions because it reaches higher levels in
Lyon, France, between 1987 and 1995. The study methods have
fetal blood and, in contrast to spiramycin, is able to penetrate
been described elsewhere.10,11 Diagnosis of maternal infection
the blood brain barrier.12 We conducted separate analyses of the
was based on: (a) detection of seroconversion (change from neg-
effect of treatment on the risks of intracranial and ocular lesions
ative to positive specific IgG antibodies); or (b) detection of IgM
and on any lesions (intracranial or ocular) detected by 3 years
specific antibodies and, low IgG avidity (Ͻ35%), and/or rising
of age (follow-up was complete for 95% of the person years of
specific IgG titre in women who were IgG positive at the first
follow-up to 3 years of age). Second, we compared the risk of
prenatal test. We excluded women referred for suspected fetal
intracranial, ocular or any lesions in children born to women
infection or abnormality based on scrutiny of referral letters or
prescribed any treatment within 4 weeks of estimated serocon-
non-sequential dates for detection of maternal infection, fetal
version with those treated 4 or more weeks after seroconversion
infection or fetal abnormalities. Spontaneous fetal losses or
terminations were excluded from the analysis as fetal inves-
We used a statistical model, previously described10,11 to take
tigations for lesions (ultrasound or autopsy) were not routinely
account of the effect of gestation at seroconversion and the
interval between seroconversion and treatment (defined as treat-ment delay) on the risk of lesions. For women who were IgG
Prenatal treatment
positive at the first prenatal test, we assumed that seroconversion
After confirmation of infection, women were prescribed
occurred between conception and the first positive test.
spiramycin (9 × 106 units/day) until delivery. If fetal diagnosis
In the analyses of the risk of intracranial lesions and of any
was positive, or maternal infection was acquired after 32 weeks,
lesion by age 3, we assumed that the effects of treatment and
treatment consisted of pyrimethamine (50 mg/day) and sulfa-
gestational age at seroconversion were additive on a logistic scale.
diazine (3 g/day) alternating 3-weekly with spiramycin until
We used a Weibull model to analyse the effect of treatment on the
delivery (subsequently referred to as pyrimethamine-sulfadiazine).
time to first detection of the first ocular lesion and assumed that
Women with confirmed fetal infection and evidence of intra-
the hazard was proportional according to treatment categories
cranial calcification or hydrocephalus on fetal ultrasound were
and gestation at seroconversion. Kaplan-Meier estimates were
used to determine the proportion of children without ocularsigns according to year of age. The association between the
Follow-up
presence of ocular and intracranial lesions was assessed using
Paediatric examinations were scheduled during the neonatal
period, at 2, 5, 8, and 12 months of age, and annually thereafter,or until congenital infection had been excluded. At each visit,
the child was examined for retinochoroidal lesions by directophthalmoscopy, usually after dilation of the iris, and a blood
Mother to child transmission of infection occurred in 194 of the
sample was taken for serology testing. Infants underwent cranial
704 infected pregnancies with complete data (Figure 1, preced-
ultrasonography or radiography or both. The dates at which
ing paper11), of which 181 resulted in a live birth. Of the
intracranial calcification, hydrocephalus or the first ocular lesion
13 non-live births, 8 fetuses were terminated after 22 weeks,
was first detected or the date of the last negative examination
5 due to hydrocephalus or ventricular dilatation on ultrasound
PRENATAL TREATMENT OF CONGENITAL TOXOPLASMOSIS
not confirmed until the next radiological examination at 3 yearsold. Two children had normal skull X-rays and ultrasound ex-aminations after birth but intracranial calcification was detectedon CT scan when they were re-examined, due to epilepsy, at 2 and 3 years of age.
Retinochoroidal lesions were detected in 37 children after a
median follow-up of 6 years 5 months. Figure 1 shows that7/181 (4%) children had lesions detected during the first monthof life, 16 (9%) by 6 months, 19 (11%) by 12 months, 29 (16%)by 3 years, 32 (19%) by 5 years and 36 (23%) by 7 years. Over-all, 21/181 children were not completely followed up to 3 years. Follow-up was complete for 95% (516/543) of the total personyears up to age 3.
Hydrocephalus, intracranial calcification, and/or ocular
lesions were detected by 3 years of age in 38/181 (21%) live-born children. Ocular lesions were more common in children
Figure 1 Time till detection of first retinochoroidal lesion in 181 children with congenital toxoplasmosis
with intracranial calcification (9/17, 53%) than in childrenwithout intracranial calcification (21/164, 13%; P = 0.0015).
Vertical lines represent 95% confidence intervals. Effect of type of treatment
There was no evidence that the risk of intracranial lesions (hydro-
scan: one also had retinochoroidal lesions detected at autopsy. Five
cephalus or intracranial calcification) was reduced in children
fetuses spontaneously aborted or were stillborn, one immediately
born to mothers prescribed pyrimethamine-sulfadiazine
after cordocentesis at 30 weeks gestation. All analyses presented
compared with those prescribed spiramycin alone (adjusted
are based on the 181 congenitally infected liveborn children.
OR = 0.90, 95% CI : 0.29, 2.64) and similarly for untreated
Prenatal treatment consisted of pyrimethamine-sulfadiazine
mothers compared with those prescribed spiramycin (adjusted
in 70/181 women (39%), spiramycin alone in 89/181 women
OR = 1.04, 95% CI : 0.05, 8.13) (Table 1). Second, there was no
(49%), and 22/181 (12%) were not treated. The estimated median
evidence that women prescribed pyrimethamine-sulfadiazine
interval between seroconversion and the start of treatment with
were less likely to have children who developed ocular lesions
pyrimethamine-sulfadiazine was 7 weeks (interquartile range
at any age compared with women prescribed spiramycin alone
[IQR] 4–10 weeks), and for spiramycin, 4 weeks (IQR 2–7 weeks).
(adjusted hazard ratio = 1.13, 95% CI : 0.56, 2.47). We estimated
All 181 infected children were treated postnatally. In 177
that if the mother seroconverted at 24 weeks gestation and gave
children, treatment was started within 2 months of birth. All
birth to an infected child, the risk of ocular lesions by age 3
but four children were prescribed pyrimethamine-sulfadiazine
years was 15.9% given spiramycin alone, and 17.7% given
and/or pyrimethamine-sulphadoxine. The median age when
pyrimethamine-sulfadiazine treatment prenatally: estimated
treatment was stopped was 22 months (IQR 17 months–
difference—1.8%, (95% CI : –12.7, 8.7%). Finally, we found no
evidence that the type of prenatal treatment had an effect onthe risk of any lesions by age 3 years (adjusted OR associated
Intracranial and ocular lesions
with pyrimethamine-sulfadiazine compared with spiramycin =
Hydrocephalus was detected after birth in two children: one
also had intracranial calcification; the other died at 8 days of agewith hepatitis and disseminated intravascular coagulation after
Effect of treatment delay on clinical signs
delivery at 34 weeks gestation, following maternal serocon-
The distribution of mother-child pairs, according to type of lesions,
version between 15 and 22 weeks and prenatal treatment with
estimated treatment delay and gestation at seroconversion is
spiramycin. Intracranial calcification was reported in a total of
shown in Figure 2. An estimated 40% (72/181) of women were
17/181 (9%) children. None of the lesions in liveborn children
treated within 4 weeks after seroconversion, 34% (58/181)
were detected prenatally. In 14 children, the first skull X-ray or
were treated between 4 and 8 weeks, and 16% (29/181) after
cranial ultrasound after birth revealed intracranial calcifications.
8 weeks or more. Of the 22 women who were not treated,
In one child, intracranial calcification was suspected at birth but
postnatal treatment was started within the first three weeks of
Table 1 Effect of prenatal treatment on intracranial and ocular lesions in children with congenital toxoplasmosis Intracranial calcification or hydrocephalus Retinochorioditis Any lesion by age 3 years Adjusted odds ratio Adjusted hazard ratio Adjusted odds ratio Treatment regimen
Note: all analyses are adjusted for gestation at seroconversion.
evidence that spiramycin compared with no treatment reducedthe risk of intracranial or ocular lesions but due to the smallsample size of the untreated group, the power to detect a sig-nificant difference between spiramycin and untreated women islow. We also found no evidence that delayed treatment (after 4or more weeks after seroconversion) or no treatment, reducedthe risk of clinical signs by 3 years of age, compared with earlytreatment (within 4 weeks of seroconversion).
Unexpectedly, the risk of intracranial lesions was significantly
reduced in children born to women treated after a delay or nottreated at all. Children born to women treated after 4 or moreweeks or not treated had a significantly lower risk of intracraniallesions, than for women treated within 4 weeks of seroconversion(adjusted OR = 0.08, 95% CI : 0.01, 0.45). This result may haveoccurred by chance and is not confirmed by preliminary find-ings from a larger, prospective European Multicentre Study onCongenital Toxoplasmosis (EMSCOT, unpublished data, R Gilbert). Figure 2 Estimated gestational age at seroconversion and treatment
We also considered alternative explanations. First, abnormal fetal
ultrasound findings may have led to prompt treatment. After
Dark grey dots = both ocular and intracranial lesions, black dots =
re-checking all patient files, we found no cases of suspected
ocular lesions by age 3, light grey dots = intracranial lesions and
fetal ultrasound abnormalities prior to diagnosis of maternal
transparent dots = no lesions detected. Treatment delay is plotted
infection. Second, we investigated whether maternal symptoms
against gestation at seroconversion. We assumed that for untreatedwomen, treatment of the child started at delivery. Both measures are
of infection could be associated with early treatment and an
based on the estimated date for seroconversion, which was a weighted
increased risk of clinical signs but found no evidence of an asso-
mean of all possible dates for each woman (weighted by the
ciation: 5% (11/181) of women reported symptoms, of whom
one gave birth to a child with signs. A third possible explanationfor the reduced risk of intracranial lesions with delayed or no
life in 19 children, after 11⁄2 months in two and after 3 months
treatment is that early treatment with pyrimethamine-sulfadiazine
suppresses the bone marrow2,p.227 and compromises the maternal
Mothers who gave birth to children with intracranial lesions
and/or fetal immune responses that limit parasite-induced cell
were significantly more likely to have seroconverted earlier in
damage.13–15 Our results need to be investigated in more power-
pregnancy (OR per week of gestation = 0.90, 95% CI : 0.84,
ful studies that can analyse the effect of early versus delayed
0.97), whereas we did not detect a significant effect of gestation
treatment according to treatment type.
at seroconversion on the risk of ocular lesions (OR = 0.97, 95%
The lack of evidence for an effect of the more potent regimen
of pyrimethamine-sulfadiazine compared with spiramycin alone
There was no evidence that delayed treatment had a signifi-
or no treatment, may be due to treatment after encystment of
cant effect on the time to detection of ocular lesions (adjusted
the parasite has occurred. Once T. gondii tachyzoites have
hazard ratio for treatment after 4 weeks/no treatment compared
crossed the placenta, transformation to the bradyzoite form can
with treatment within 4 weeks of seroconversion = 0.69, 95%
occur within days,16 probably due to stresses caused by the
CI : 0.28, 1.68) or on the risk of any lesions by 3 years of age
humoral and cell mediated immune responses.17 Neither
(adjusted OR = 0.44, 95% CI : 0.16, 1.19).
spiramycin nor pyrimethamine-sulfadiazine is effective against
As treatment may have an effect on mother to child transmis-
the encysted, bradyzoite form of the parasite, although
sion, we determined the overall effect of early (within 4 weeks
experimental studies show that both are effective against the
of seroconversion) compared with delayed or no treatment on
free tachyzoite form.12 As treatment is always given some time,
the risk of lesions by 3 years of age in infected and uninfected
often weeks, after maternal antibodies develop, it may be
children born to seroconverting women (see preceding paper11).
given after encystment of the parasite. Due to limitations
The adjusted OR for any lesion at 3 years associated with delayed
of sample size and the fact that few women receive
or no treatment compared with early treatment was 0.63 (95%
pyrimethamine/sulfadiazine immediately after detection of
maternal seroconversion, we could not investigate the effects oftiming of different types or dosages of treatment.
We found a significant effect of gestation at maternal sero-
conversion on the risk of intracranial lesions, but a less marked
We have analysed the largest reported cohort of children with
effect on the risk of ocular lesions. These findings may reflect
congenital toxoplasmosis, taking care to minimize selection bias
differing immune responses at the two sites resulting in differ-
due to women with affected fetuses, and taking account of the
effect of gestation at maternal seroconversion on the risk oflesions.10 We found no evidence that prenatal treatment with
pyrimethamine-sulfadiazine compared with spiramycin reducedthe risk of intracranial or ocular lesions although the 95% CI
Our study failed to detect a beneficial effect of prenatal treat-
included both beneficial and harmful effects. There was also no
ment on the risk of clinical signs in infected children. Although
PRENATAL TREATMENT OF CONGENITAL TOXOPLASMOSIS
ours is the largest study to date to address this question, the
and Environmental Protection (Netherlands), ISBN 90–9004179–6.
confidence intervals for the effects of different types of treat-
ment are wide. Consequently, we cannot exclude potentially
6 Koppe JG, Loewer Sieger DH, de Roever Bonnet H. Results of 20-year
beneficial or harmful effects. The significant finding of a beneficial
follow-up of congenital toxoplasmosis. Lancet 1986;i:254–56.
effect of delayed treatment on intracranial lesions may be
7 Berrebi A, Kobuch WE, Bessieres MH et al. Termination of pregnancy
due to chance and requires confirmation by further studies. A
for maternal toxoplasmosis. Lancet 1994;344:36–39.
further concern is the lack of information on the association
8 Foulon W, Villena I, Stray-Pedersen, B et al. Treatment of toxo-
between intracranial lesions and subsequent developmental
plasmosis during pregnancy: a multicentre study of impact on fetal
impairment. Larger, prospective studies, which determine the
transmission and children’s sequelae at age 1 year. Am J Obstet Gynecol 1999;180:410–15.
effect of prenatal treatment on long-term developmental
outcomes are therefore required to justify changes in clinical
Couvreur J, Thulliez P, Daffos F et al. In utero treatment of toxoplasmicfetopathy with the combination pyrimethamine-sulfadiazine. FetalDiagn Ther 1993;8:45–50.
10 Dunn D, Wallon M, Peyron F, Petersen E, Peckham CS, Gilbert RE.
Mother to child transmission of toxoplasmosis: risk estimates for clinical counselling. Lancet 1999;353:1829–33.
The study was funded by The Wellcome Trust and by the Euro-
11 Gilbert RE, Gras L, Wallon M, Peyron F, Ades AE, Dunn, D. Effect of
pean Commission BIOMED programme (BMH4-CT98–3927).
prenatal treatment on mother to child transmission of Toxoplasma
We thank the staff of Laboratoire de Parasitologie et de Pathologie
gondii: a cohort study of 554 mother-child pairs in Lyon, France. Int J
Exotique, Hôpital de la Croix Rousse, Lyon, for help with data
Epidemiol 2001;30:1303–08.
collection and Eskild Petersen for helpful comments on drafts of
12 Derouin F. Drugs effective against Toxoplasma gondii. Present status
the report and facilitating the collaboration. We thank Martine
and future perspective. In: Amboise-Thomas P, Petersen E (eds).
Wallon and Francois Peyron for providing the data and for
Congenital Toxoplasmosis. Scientific Background, Clinical Management and
contributing to the design, execution and interpretation of the
Control. Paris: Springer Verlag, 2000, pp.95–110.
study. The conclusions in this paper do not reflect the opinions
McLeod R, Dowel M. Basic immunology: fetus and the newborn. In:
of the clinicians in the department which provided the data.
Amboise-Thomas P, Petersen E (eds). Congenital Toxoplasmosis. ScientificBackground, Clinical Management and Control. Paris: Springer Verlag,2000, pp.37–68.
Alexander J, Roberts CW, Walker W, Reichmann G, Hunter CA. Theimmunology of Toxoplasma gondii infection in the immune-competent
1 Jeannel D, Costagliola D, Niel G, Hubert B, Danis M. What is known
host. In: Amboise-Thomas P, Petersen E (eds). Congenital Toxoplasmosis.
about the prevention of congenital toxoplasmosis? Lancet 1990;336: Scientific Background, Clinical Management and Control. Paris: Springer
2 Remington JS, McLeod R, Desmonts G. Toxoplasmosis. In: Remington
15 Dammann O, Leviton A. Infection remote from the brain, neonatal
JS, Klein J (eds). Infectious Diseases of the Fetus and Newborn. 4th Edn.
white matter damage, and cerebral palsy in the preterm infant. Semin
Pennsylvania: WB Saunders, 1995, pp.140–267. Pediatr Neurol 1998;5:190–201.
3 Guerina NG, Hsu HW, Meissner HC et al. Neonatal serologic screening
16 Luder CGK, Giraldo Velasquez MA, Sendtner M, Gross U. Toxoplasma
and early treatment for congenital Toxoplasma gondii infection. The
gondii in primary rat CNS cells: differential contribution of neurons,
New England Regional Toxoplasma Working Group. N Engl J Med
astrocytes, and microglial cells for the intracerebral development and
1994;330:1858–63.
stage differentiation. Exp Parasitol 1999;93:23–32.
4 Lebech M, Andersen O, Christensen NC et al. Feasibility of neonatal
17 Roberts F, McLeod R. Pathogenesis of toxoplasmic retinochoroiditis.
screening for toxoplasma infection in the absence of prenatal
Parasitol Today 1999;15:51–57.
treatment. Lancet 1999;353:1834–37.
18 Brezin AP, Kasner L, Thulliez P et al. Ocular toxoplasmosis in the fetus.
5 Conyn-van-Spaedonck MAE. Prevention of Congenital Toxoplasmosis
immunohistochemistry analysis and DNA amplification. Retina 1994;
in the Netherlands (Thesis). National Institute of Public Health
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International Epidemiological Association 2001
International Journal of Epidemiology 2001;30:1314–1315 Commentary: Little evidence of effective prenatal treatment against congenital toxoplasmosis—the implications for testing in pregnancy
Testing for antibodies against Toxoplasma gondii in pregnancy is
includes children of all seroconverting women in the analysis
routinely offered in some countries. However, no randomized
(the outcome is a combination of risk of transmission and risk
controlled trials of the effect of treatment have been performed,
of sequellae given transmission). If the latter study3 had limited
and the question of whether testing in pregnancy should be
the analysis to children under direct risk, it appears from inspec-
encouraged rests on evidence from observational studies. Two
tion of the reported data that the protective effect would have
such studies are presented in this issue. The first investigated
been smaller and insignificant, although this cannot be directly
the effect of timing and type of treatment on the risk of vertical
judged since the distribution of gestational age at infection (the
transmission.1 The authors hypothesize that the lack of effect
main confounder) is not presented by treatment group. A major
in their study is explained by rapid transmission to the fetus
problem with all the observational studies is the selection of
after maternal infection, implying that the initiation of treatment
patients to treatment, and given treatment, the selection to
short or long time intervals before treatment starts.
The other study estimates the impact of timing and type of
treatment on the risk of intracranial and ocular lesions in con-
genitally infected children at 3 years of age.2 Even after controllingfor the length of gestation at maternal infection, they found a
The observational studies discussed above do not provide con-
paradoxical effect of treatment. A long interval from serocon-
vincing evidence for beneficial effects of prenatal treatment of
version to treatment lowered the risk of intracranial lesions,
toxoplasmosis. Treatment in pregnancy should, in our opinion,
whereas the opposite would be expected. The interval seemed
be regarded as experimental, and only be performed as part of
to have no impact on the risk of ocular lesions and the type of
carefully conducted randomized trials.
treatment did not seem to influence the risk of congenital
Even if there were a beneficial effect of treatment in preg-
damage. The authors state that their results provide no evidence
nancy, there may not be an overall positive effect of screening.
that prenatal screening is beneficial.
The effect of screening depends on the magnitude of the healthproblem, the estimated treatment effect, but also on the com-pliance to the screening programme and the treatment.5 Also,
possible side effects of treatment must also be considered, as dis-
The finding of no treatment effect on the transmission rate is in
cussed by Gras et al. on the basis of their findings.2 Pyrimethamine
agreement with a recent European multicentre study including
is a folic acid antagonist. The use of folic acid antagonists in
144 infected women,3 and with systematic literature reviews.4,5
pregnancy has been associated with increased risk of neural
However, estimates of transmission rates vary widely. In the
tube defects.7 Termination of pregnancy with a healthy fetus
present study,1 the proportion of infected children was 28%,
and complications to invasive prenatal diagnosis are other im-
while it was 19% in a large population-based Danish study.6
portant potential side effects. In addition to the economic costs
In the multicentre study,3 the transmission rate varied from
and the use of limited health resources, which traditionally
30% to 73% between centres, with an overall value of 44%.
have been in focus when debating screening initiation, the
This variability raises issues of inter-study differences in
psychological aspects have come increasingly into focus.8 Initial
selection of cases or differences in laboratory methods.
false positive diagnoses are common when screening for disorders
The finding in the second study2 that treatment has no
of low prevalence. Both false and verified positive diagnoses
beneficial effect on sequellae is in contrast to the results from
may cause anxiety in the mother and her family throughout the
the multicentre study,3 where a significant, protective effect of
pregnancy and reduce the positive expectations for the new
treatment is reported. The studies differ in their analytical
child, even though the risk of a severely diseased child is low.
approach. The study by Gras et al.2 includes only outcomes in
On this background, should one commence health district-
children where transmission has occurred (i.e. the children who
randomized controlled trials on the effect of introducing a screen-
are at direct risk of sequellae), while the multicentre study3
ing programme of testing in pregnancy? In today’s situation,with little evidence of any beneficial effect of treatment, ouropinion is no. First, one should document that treatment is
Section of Epidemiology, National Institute of Public Health, PO Box 4404Nydalen, 0403 Oslo, Norway.
PRENATAL TREATMENT OF CONGENITAL TOXOPLASMOSIS
2 Gras L, Gilbert RE, Ades AE, Dunn DT. Effect of prenatal treatment on
the risk of intracranial and ocular lesions in children with congenital
We suggest that the effect of prenatal treatment should be tested
toxoplasmosis. Int J Epidemiol 2001;30:1309–13.
out using an ordinary double-blind placebo-controlled clinical
3 Foulon W, Villena I, Stray-Pedersen B et al. Treatment of toxoplasmosis
trial with randomization on an individual basis.
during pregnancy: a multicenter study of impact on fetal transmission
Additionally, better estimates of the burden of disease should
and children’s sequelae at one year of age. Am J Obstet Gynecol 1999;
be made, including population statistics. How many children
180:410–15.
in a certain population will suffer from the consequences of
4 Wallon M, Liou C, Garner P, Peyron F. Congenital toxoplasmosis:
congenital toxoplasmosis? The observational studies give little
systematic review of evidence of efficacy of treatment in pregnancy.
detail as to the degree of disability and illness experienced by
Br Med J 1999;318:1511–14.
these children. Such data are also needed for evaluation of public
5 Eskild A, Oxman A, Magnus P, Bjørndal A, Bakketeig LS. Screening
for toxoplasmosis in pregnancy: what is the evidence of reducing a
We also suggest that controlled community trials could be
health problem? J Med Screening 1996;3:188–94.
performed to estimate the effect of primary prevention directed
Lebech M, Andersen O, Christensen NC et al. Feasibility of neonatal
against established risk factors.9 Thus, one could randomize health
screening for toxoplasma infection in the absence of prenatal treat- ment. Lancet 1999;353:1834–37.
care districts to have intervention or no intervention, where the
intervention might consist of detailed advice to women in early
Hernandez-Diaz S, Werler MM, Walker AM, Mitchell AA. Neural tubedefects in relation to use of folic acid antagonists during pregnancy.
pregnancy to modify behaviour with respect to consumption
Am J Epidemiol 2001;153:961–68.
of raw or undercooked meat and unwashed vegetables, and
8 Stewart-Brown S, Farmer A. Screening could seriously damage your
behaviour with respect to contact with cat faeces.
health. Br Med J 1997;314:533–34.
9 Kapperud G, Jenum PA, Stray-Pedersen B, Melby K, Eskild A, Eng J.
Risk factors for toxoplasma infection in pregnancy. Results from a prospective study in Norway. Am J Epidemiol 1996;144:405–12.
1 Gilbert RE, Gras L, Wallon M, Peyron F, Ades AE, Dunn DT. Effect of
prenatal treatment on mother to child transmission of Toxoplasma gondii: retrospective cohort study of 544 mother-child pairs in Lyon, France. Int J Epidemiol 2001;30:1303–08.
International Epidemiological Association 2001
International Journal of Epidemiology 2001;30:1315–1316 Commentary: Efficacy of prenatal treatment for toxoplasmosis: a possibility that cannot be ruled out
In their retrospective cohort study of 554 mother-child pairs,
A further problem is that most of the untreated women were
Gilbert et al. did not detect a significant effect of prenatal
infected during the third trimester of pregnancy. Figure 4 shows
treatment on the risk of vertical transmission of toxoplasmosis.1
that only three women infected before 28 weeks of gestation
This result is not surprising as there were very few untreated
were not treated. The remaining 28 untreated women were
women and the analysis of no treatment versus pyrimethamine-
infected after 28 weeks. The effect of treatment in the third
sulphadiazine was restricted to half of the cohort who did not
trimester cannot be generalized to the whole of pregnancy.
undergo amniocentesis. The confidence interval (0.37–3.03) Finally, the authors explain their findings by suggesting thatfor the odds ratio (1.06) for no treatment compared with
vertical transmission occurs soon after infection, during para-
pyrimethamine-sulphadiazine was therefore very wide and
sitaemia. This hypothesis is not supported by any scientific
could include a doubling in the risk of transmission in untreated
studies in humans. On the contrary, one study found that the
women. Thus an absence of evidence of prenatal treatment
sensitivity of prenatal diagnosis was lower in early than mid
effect does not exclude a clinically important beneficial effect.
pregnancy, suggesting that vertical transmission may be delayedfor some women infected in early pregnancy.2
In the second report by Gras et al.,3 the authors unexpectedly
found no evidence that prenatal treatment with pyrimethamine-
Laboratoire de la Toxoplasmose, Institut de Puériculture, Paris, France.
sulphadiazine was more effective than spiramycin in reducing
the risks of intracranial or ocular lesions in congenitally infected
spiramycin. The periods of spiramycin treatment may have led
infants by 3 years of age. A potential explanation for this result
to parasitic relapses in fetal tissues, as shown in experimental
is that mothers who transmitted the infection to their fetus
models.6 The current treatment policy for women with a positive
soon after infection were more likely to be treated with
prenatal diagnosis is to prescribe continuous treatment with
pyrimethamine-sulphadiazine than mothers infected at the same
pyrimethamine-sulphadiazine until delivery. The data reported
gestation but in whom transmission was delayed until later in
by Gilbert et al.1 and Gras et al.3 provide no convincing evidence
pregnancy. These two groups may not be comparable as fetuses
infected earlier in pregnancy have a higher risk of clinical signs. This explanation is suggested by the fact that mothers infectedbefore 32 weeks were only given pyrimethamine-sulphadiazine
if the diagnosis of fetal infection was positive (i.e vertical trans-
1 Gilbert RE, Gras L, Wallon M, Peyron F, Ades AE, Dunn DT. Effect of
mission occurred between maternal infection and the date of
prenatal treatment on mother to child transmission of Toxoplasma
fetal sampling). Other mothers infected before 32 weeks were
gondii: retrospective study of 554 mother-child pairs in Lyon, France.
treated with spiramycin until delivery, either because the pre-
Int J Epidemiol 2001;30:1303–08.
natal diagnosis was negative or not attempted. In this latter
2 Romand S, Wallon M, Franck J, Thulliez P, Peyron F, Dumon H.
group, transmission occurred either after amniocentesis or at
Prenatal diagnosis using polymerase chain reaction on amniotic fluid
some unknown time between the date of maternal infection
for congenital toxoplasmosis. Obstet Gynecol 2001;97:296–300.
and delivery, that is later during gestation than in the group
3 Gras L, Gilbert RE, Ades AE, Dunn DT. Effect of prenatal treatment on
receiving pyrimethamine-sulphadiazine.
the risk of intracranial and ocular lesions in children with congenital
There are two further explanations for the lack of effect of
toxoplasmosis. Int J Epidemiol 2001; 30:1309–13.
pyrimethamine-sulphadiazine. Firstly, there was a long delay
Dunn D, Wallon M, Peyron F, Petersen E, Peckham C, Gilbert R.
before pyrimethamine-sulphadiazine was started. This was
Mother-to-child transmission of toxoplasmosis: risk estimates for clinical counselling. Lancet 1999;353:1829–33.
because the study was carried out more than 6 years ago, when
mouse inoculation was the standard fetal diagnostic test4
Hohlfeld P, Daffos F, Costa JM, Thulliez P, Forestier F, Vidaud M. Prenatal diagnosis of congenital toxoplasmosis with a polymerase-
and pyrimethamine-sulphadiazine treatment would have been
chain-reaction test on amniotic fluid. N Engl J Med 1994;331:
delayed for 3–6 weeks until results were known. Today, PCR
analysis of amniotic fluid is widespread. Results are available
6 Piketty C, Derouin F, Rouveix B, Pocidalo JJ. In vivo assessment
in one day and women with infected fetuses are treated much
of antimicrobial agents against Toxoplasma gondii by quantification of
earlier.5 Secondly, women in the study given pyrimethamine-
parasites in the blood, lungs, and brain of infected mice. Antimicrob
sulphadiazine actually received an alternating regimen with
Agents Chemother 1990;34:1467–72.
Trust Guideline All Sites Guidance on Prescribing in Situations not covered by the NHS All healthcare professionals must exercise their own professional judgement when using guidelines. However any decision to vary from the guideline should be documented in the patient records to include the reason for variance and the subsequent action taken. 2010 or sooner in respons
ARTICLES CYSTINOSIS AND ITS TREATMENT By D. Cairns, PhD, MRPharmS, R. J. Anderson, PhD, MRSC, M. Coulthard, MB ChB, and J. Terry Cystinosis is a rare inherited disease with an incidence, in developed countries, of about one case in every 200,000 live births. In the past, it was rare for cystinosis sufferers to survive into adulthood. The disease occurs when the mechanism that